Definitive treatment of Graves’ disease in children

BACKGROUND: Hyperthyreoidism due to Graves’ disease is a rare disorder in pediatric practice. There is 2 treatment options in Graves’ disease: medical treatment and definitive treatment, including surgery and radioactive iodine. Each method has its advantages and disadvantages. If medical therapy is ineffective the choice between radical treatment method is raised: radioactive iodine or total thyroidectomy. In this research we analyze treatment outcomes in pediatric Graves’ disease patients after different radical treatment methods.

AIM: Comparative analysis of radical treatment outcomes in pediatric patients with Graves’ disease.

MATERIALS AND METHODS: Retrospective and prospective one-center research of 122 patients with Graves’ disease after radical treatment (between 2016 and 2021)

RESULTS: The mean age was 13.5±3,5 year at the moment of examination. Patients were divided into 2 groups due to the radical treatments method: 1 group (n=60) were children after surgical treatment, 2 group (n=62) — after radioactive iodine. The mean dose of medical treatment in these groups did not reliably differ (p=0,06), duration of the medical treatment was reliably longer in patients after radioactive iodine (p=0,024). Graves’ orbitopathy was diagnosed in 58 patients (47,5%) and met equally often in both groups, but active stage of Graves’ orbitopathy was diagnosed only in patients from the 1st group. Thyroid size was reliable bigger in patients from the 1st group (p=0,004), and thyroid gland nodes were diagnosed only in patients from 1st group (p=0,0007).

CONCLUSION: RI can be considered an effective and safe treatment for GD. The effectiveness of RI depends on the volume of the thyroid gland; according to the results of the constructed ROC curve, the risk of repeated RI is higher with a volume of more than 55 cm3. Also radioactive iodine is undesirable if there is signs of ophatalmopathy due to its possible deterioration. According to the results of the study hypoparathyroidism after surgical treatment was diagnosed in 20%, recurrent laryngeal nerve injury was diagnosed after surgical treatment in 5% of patients. In patients with identified nodular goiter according to the results of ultrasound, surgical treatment is preferable due to the impossibility of excluding thyroid cancer.

1. Abraham-Nordling M, Byström K, Törring O, et al. Incidence of hyperthyroidism in Sweden. Eur J Endocrinol. 2011;165(6):899-905. doi: https://doi.org/10.1530/EJE-11-0548

2. Simon M, Rigou A, Le Moal J, et al. Epidemiology of Childhood Hyperthyroidism in France: A Nationwide Population-Based Study. J Clin Endocrinol Metab. 2018;103(8):2980-2987. doi: https://doi.org/10.1210/jc.2018-00273

3. Williamson S, Greene SA. Incidence of thyrotoxicosis in childhood: a national population based study in the UK and Ireland. Clin Endocrinol (Oxf). 2010;72(3):358-363. doi: https://doi.org/10.1111/j.1365-2265.2009.03717.x

4. Kaguelidou F, Alberti C, Castanet M, et al. Predictors of Autoimmune Hyperthyroidism Relapse in Children after Discontinuation of Antithyroid Drug Treatment. J Clin Endocrinol Metab. 2008;93(10):3817-3826. doi: https://doi.org/10.1210/jc.2008-0842

5. Wong GWK, Cheng PS. Increasing incidence of childhood Graves’ disease in Hong Kong: A follow-up study. Clin Endocrinol (Oxf). 2001;54(4):547-550. doi: https://doi.org/10.1046/j.1365-2265.2001.01252.x

6. Rodanaki M, Lodefalk M, Forssell K, et al. The Incidence of Childhood Thyrotoxicosis Is Increasing in Both Girls and Boys in Sweden. Horm Res Paediatr. 2019;91(3):195-202. doi: https://doi.org/10.1159/000500265

7. Federal’nye klinicheskie rekomendatsii (protokoly) po vedeniyu detei s endokrinnymi zabolevaniyami. Ed by Dedov II, Peterkova VA. — Moscow: Praktika; 2014. P. 215-239. (In Russ.).

8. БBezlepkina OB. Federal clinical recommendations on diagnostics and treatment of Graves’ disease in the children. Problems of Endocrinology. 2014;60(3):59-68. (In Russ.). doi: https://doi.org/10.14341/probl201460359-68

9. van Lieshout JM, Mooij CF, van Trotsenburg ASP, Zwaveling-Soonawala N. Methimazole-induced remission rates in pediatric Graves’ disease: a systematic review. Eur J Endocrinol. 2021;185(2):219-229. doi: https://doi.org/10.1530/EJE-21-0077

10. Kaguelidou F, Alberti C, Castanet M, et al. Predictors of Autoimmune Hyperthyroidism Relapse in Children after Discontinuation of Antithyroid Drug Treatment. J Clin Endocrinol Metab. 2008;93(10):3817-3826. doi: https://doi.org/10.1210/jc.2008-0842

11. Léger J, Gelwane G, Kaguelidou F, et al. Positive Impact of Long-Term Antithyroid Drug Treatment on the Outcome of Children with Graves’ Disease: National Long-Term Cohort Study. J Clin Endocrinol Metab. 2012;97(1):110-119. doi: https://doi.org/10.1210/jc.2011-1944

12. Gostimskii AV, Peredereev SS. Sovremennye problemy khirurgicheskogo lecheniya bol’nykh diffuznym toksicheskim zobom detskogo vozrasta. Pediatr. 2013;4:69-76. (In Russ.).

13. Rumiantsev PO, Kiyaev AV, Sehemeta MS, Chikulaeva OA. Radioiodine therapy of thyrotoxicosis in children and adolescents. Indications, efficacy and safety. Literature review. Endocrine Surgery. 2016;10(4):6-12. (In Russ.). doi: https://doi.org/10.14341/serg201646-12

14. Bahn RS. Graves’ Ophthalmopathy. N Engl J Med. 2010;362(8):726-738. doi: https://doi.org/10.1056/NEJMra0905750;

15. Prasai A, Nix PA, Aye M, et al. Total thyroidectomy for safe and definitive management of Graves’ disease. J Laryngol Otol. 2013;127(7):681-684. doi: https://doi.org/10.1017/S0022215113001254

16. Quérat C, Germain N, Dumollard J-M, et al. Surgical management of hyperthyroidism. Eur Ann Otorhinolaryngol Head Neck Dis. 2015;132(2):63-66. doi: https://doi.org/10.1016/j.anorl.2014.04.005

17. Edafe O, Antakia R, Laskar N, et al. Systematic review and meta-analysis of predictors of post-thyroidectomy hypocalcaemia. Br J Surg. 2014;101(4):307-320. doi: https://doi.org/10.1002/bjs.9384

18. Burch HB, Cooper DS. Management of Graves Disease. JAMA. 2015;314(23):2544-2554. doi: https://doi.org/10.1001/jama.2015.16535

19. Genovese BM, Noureldine SI, Gleeson EM, et al. What Is the Best Definitive Treatment for Graves’ Disease? A Systematic Review of the Existing Literature. Ann Surg Oncol. 2013;20(2):660-667. doi: https://doi.org/10.1245/s10434-012-2606-x

20. Brito JP, Schilz S, Singh Ospina N, et al. Antithyroid Drugs—The Most Common Treatment for Graves’ Disease in the United States: A Nationwide Population-Based Study. Thyroid. 2016;26(8):1144-1145. doi: https://doi.org/10.1089/thy.2016.0222

21. Aung ET, Zammitt NN, Dover AR, et al. Predicting outcomes and complications following radioiodine therapy in Graves’ thyrotoxicosis. Clin Endocrinol (Oxf). 2019;90(1):192-199. doi: https://doi.org/10.1111/cen.13873

22. Sirianong N, Kevalee U, Prapai D, et al. Radioactive Iodine for Thyrotoxicosis in Childhood and Adolescence: Treatment and Outcomes. J Clin Res Pediatr Endocrinol. 2013;5(2):95-97. doi: https://doi.org/10.4274/Jcrpe.951

23. Azizi F, Amouzegar A. Management of thyrotoxicosis in children and adolescents: 35 years’ experience in 304 patients. J Pediatr Endocrinol Metab. 2018;31(2):159-165. doi: https://doi.org/10.1515/jpem-2017-0394

24. Allahabadia A, Daykin J, Sheppard MC, et al. Radioiodine Treatment of Hyperthyroidism—Prognostic Factors for Outcome. J Clin Endocrinol Metab. 2001;86(8):3611-3617. doi: https://doi.org/10.1210/jcem.86.8.7781

25. Prasai A, Nix PA, Aye M, et al. Total thyroidectomy for safe and definitive management of Graves’ disease. J Laryngol Otol. 2013;127:681-684. doi: https://doi.org/10.1017/S0022215113001254

26. Quérat C, Germain N, Dumollard J-M, et al. Surgical management of hyperthyroidism. Eur Ann Otorhinolaryngol Head Neck Dis. 2015;132(2):63-66. doi: https://doi.org/10.1016/j.anorl.2014.04.005

27. Phitayakorn R, Morales-Garcia D, Wanderer J, et al. Surgery for Graves’ disease: a 25-year perspective. Am J Surg. 2013;206(5):669-673. doi: https://doi.org/10.1016/j.amjsurg.2013.07.005

28. Catania A, Guaitoli E, Carbotta G, et al. Total thyroidectomy for Graves’ disease treatment. Clin Ter. 2013;164:193-196. doi: https://doi.org/10.7417/CT.2013.1548

29. Genovese BM, Noureldine SI, Gleeson EM, et al. What Is the Best Definitive Treatment for Graves’ Disease? A Systematic Review of the Existing Literature. Ann Surg Oncol. 2013;20(2):660-667. doi: https://doi.org/10.1245/s10434-012-2606-x

30. Liu ZW, Masterson L, Fish B, Jani P, Chatterjee K. Thyroid surgery for Graves’ disease and Graves’ ophthalmopathy. Cochrane Database Syst Rev. 2015. doi: https://doi.org/10.1002/14651858.CD010576.pub2

31. Burch HB, Cooper DS. Management of Graves Disease. JAMA. 2015;314(23):2544-2554. doi: https://doi.org/10.1001/jama.2015.16535

32. Edafe O, Antakia R, Laskar N, et al. Systematic review and meta-analysis of predictors of post-thyroidectomy hypocalcaemia. Br J Surg. 2014;101(4):307-320. doi: https://doi.org/10.1002/bjs.9384

33. Oltmann SC, Brekke AV, Schneider DF, et al. Preventing Postoperative Hypocalcemia in Patients with Graves Disease: A Prospective Study. Ann Surg Oncol. 2015;22(3):952-958. doi: https://doi.org/10.1245/s10434-014-4077-8

34. Bellantone R, Lombardi CP, Bossola M, et al. Total thyroidectomy for management of benign thyroid disease: Review of 526 cases. World J Surg. 2002;26(12):1468-1471. doi: https://doi.org/10.1007/s00268-002-6426-1

35. Efremidou EI, Papageorgiou MS, Liratzopoulos N, Manolas KJ. The efficacy and safety of total thyroidectomy in the management of benign thyroid disease: a review of 932 cases. Can J Surg. 2009;52(1):39-44.

36. Desforges JF, Mazzaferri EL. Management of a Solitary Thyroid Nodule. N Engl J Med. 1993;328(8):553-559. doi: https://doi.org/10.1056/NEJM199302253280807

37. Tufano RP, Noureldine SI, Angelos P. Incidental Thyroid Nodules and Thyroid Cancer. JAMA Otolaryngol Neck Surg. 2015;141(6):566. doi: https://doi.org/10.1001/jamaoto.2015.0647

38. Wei S, Baloch ZW, LiVolsi VA. Thyroid Carcinoma in Patients with Graves’ Disease: an Institutional Experience. Endocr Pathol. 2015;26(1):48-53. doi: https://doi.org/10.1007/s12022-014-9343-6

39. Kitahara CM, Sosa JA. The changing incidence of thyroid cancer. Nat Rev Endocrinol. 2016;12(11):646-653. doi: https://doi.org/10.1038/nrendo.2016.110

40. McLeod DSA, Watters KF, Carpenter AD, et al. Thyrotropin and Thyroid Cancer Diagnosis: A Systematic Review and Dose-Response Meta-Analysis. J Clin Endocrinol Metab. 2012;97(8):2682-2692. doi: https://doi.org/10.1210/jc.2012-1083

41. Boostrom S, Richards ML. Total thyroidectomy is the preferred treatment for patients with Graves’ disease and a thyroid nodule. Otolaryngol Neck Surg. 2007;136(2):278-281. doi: https://doi.org/10.1016/j.otohns.2006.09.011

42. Rinaldi S, Plummer M, Biessy C, et al. Thyroid-Stimulating Hormone, Thyroglobulin, and Thyroid Hormones and Risk of Differentiated Thyroid Carcinoma: The EPIC Study. JNCI J Natl Cancer Inst. 2014;106(6). doi: https://doi.org/10.1093/jnci/dju097

43. Huang H, Rusiecki J, Zhao N, et al. Thyroid-Stimulating Hormone, Thyroid Hormones, and Risk of Papillary Thyroid Cancer: A Nested Case–Control Study. Cancer Epidemiol Biomarkers Prev. 2017;26(8):1209-1218. doi: https://doi.org/10.1158/1055-9965.EPI-16-0845

44. Dal Maso L, Bosetti C, La Vecchia C, Franceschi S. Risk factors for thyroid cancer: an epidemiological review focused on nutritional factors. Cancer Causes Control. 2009;20(1):75-86. doi: https://doi.org/10.1007/s10552-008-9219-5

45. Shaha AR. Controversies in the Management of Thyroid Nodule. Laryngoscope. 2000;110(2):183-183. doi: https://doi.org/10.1097/00005537-200002010-00001

46. Becker D V. Choice of Therapy for Graves’ Hyperthyroidism. N Engl J Med. 1984;311(7):464-466. doi: https://doi.org/10.1056/NEJM198408163110710

47. Kung AW, Yau CC, Cheng A. The incidence of ophthalmopathy after radioiodine therapy for Graves’ disease: prognostic factors and the role of methimazole. J Clin Endocrinol Metab. 1994;79(2):542-546. doi: https://doi.org/10.1210/jcem.79.2.7913934

48. Bartalena L, Marcocci C, Bogazzi F, et al. Relation between therapy for hyperthyroidism and the course of Graves’ ophthalmopathy. N Engl J Med. 1998;338:73-78. doi: https://doi.org/10.1056/NEJM199801083380201

49. Rivkees SA, Dinauer C. An Optimal Treatment for Pediatric Graves’ Disease Is Radioiodine. J Clin Endocrinol Metab. 2007;92(3):797-800. doi: https://doi.org/10.1210/jc.2006-1239